Benzothiazepines and benzothiazocines



United States Patent Oflice Int. Cl. C07c 93/40 US. Cl. 260-327 3 ClaimsABSTRACT OF THE DISCLOSURE Compounds of the formula wherein Y is S, SOor S, R is lower alkyl, lower alkenyl, aralkyl or aralkenyl; R ishydrogen or lower alkyl; X and X are the same or different and arehydrogen, lower alkyl, lower alkoxy, amino, dialkylamino, halo, loweralkylthio, hydroxy, cyano, nitro or trifluoromethyl; A is loweralkylene; B is a basic nitrogen containing radical having less thantwelve carbon atoms; p is an integer from one to three; one It is oneand the other n is Zero or one, and salts thereof are prepared. Thesenew compounds are useful as tranquilizers, inter alia.

This application is a division of my application Ser. No. 569,020, filedAug. 1, 1966, now US. Pat. 3,401,166.

The therapeutically active compounds of this invention are of thegeneral formula wherein Y is selected from the group consisting of thia(S), sulfone (SO sulfoxide (SO) and oxa (O); R is selected from thegroup consisting of lower alkyl, lower alkenyl, aralkyl or aralkenyl; Ris selected from the group consisting of hydrogen and lower alkyl; X andX may be the same or different and are selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, amino, dialkylamino,halo, lower alkylthio (e.g., CH CH CH S), hydroxy, cyano, nitro andtrifiuoromethyl; A represents lower alkylene; B is a basic nitrogencontaining radical having less than twelve carbons; p is an integer fromone to three and n represents or 1, and to salts thereof.

Among the suitable radicals represented by the symbol B are: amino;(lower alkyl)amino; di(lower alkyl) 3,535,338 Patented Oct. 20, 1970amino; (hydroxylower alkyl)amino; di(hydroxylower a1kyl)amino;phenyl(lower alkyl)amino; N-(lower alky1)phenyl (lower alkyl)amino; andsaturated 5- or 7-membered monocyclic heterocyclic radicals of less thantwelve carbon atoms, as exemplified by piperidino; (loweralkyl)piperidino; di(lower alkyl)piperidino; (lower alkoxy)piperidino;homopiperidino; 2,3- or 4-piperidyl; 2,3- or 4-(N-lower alkylpiperidyl);pyrrolidino; (lower alkyl)pyrrolidino; di(lower alkyl)pyrrolidino;(lower alkoxy)pyrrolidino; 2- or 3-pyrrolidyl; 2- or 3-(N-1ower alkylpyrrolidyl); morpholino; (lower alkyl)morpholino; di(loweralkyl)morpholino; (lower alkoxy)morpholino; thiamorpholino; (loweralkyl)thiamorpholino; di(lower alkyl)thiamorpholino; (loweralkoxy)thiamorpholino; piperazino; 4-Rsubstituted piperazino (e.g., N-ethylpiperazino; N phenylpiperazino, and so forth); [hydroXy (loweralkyl)]piperazino [e.g., N -(2 hydroxyethyl)piperazino]; (loweralkyl)piperazino (e.g., N methylpiperazino); di(lower alkyl)piperazino;(lower alkoxy)piperazino; homopiperazino; and 4-Rsubstitutedhomopiperazino (e.g., N -benzylhomopiperazino).

The terms lower alkyl, lower alkoxy, and lower alkylene, as employedherein, include both straight and branched chain radicals of less thaneight carbon atoms, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, amyl, methoxy, ethoxy, propoxy, isopropoxy,ethylene, propylene, and the like.

The term ary as employed herein includes mononuclear and dinuclearradicals such as X-substituted phenyl (including3,4-methylenedioxyphenyl and 3,4- ethylenedioxyphenyl), furyl, thienyl,naphthyl or pyridyl.

The particularly preferred compounds are those wherein X and X arehydrogen, Y is Sulfur or oxygen, R is lower alkyl, R is hydrogen, A isethylene, B is dimethylamino and both ns are 0.

As to the salts, those coming within the purview of this inventioninclude the acid-addition salts of those compounds containing a basicgroup particularly the nontoxic acid-addition salts and the quaternaryammonium salts. Acids useful for preparing these acid-addition saltsinclude, inter alia, inorganic acids, such as the hydrohalic acids(e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid,and phosphoric acid, and organic acids such as maleic, tartaric, citric,acetic, salicylic, succinic acid, theophylline, 8 chlorotheophylline,benzoic, nicotinic, methanesulfonic or cyclohexanesulfamic. Thequaternary ammonium salts include those formed with alkyl halides (e.g.,methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide),benzyl halides (e.g., benzyl chloride) and dilower alkyl sulfates (e.g.,dimethyl sulfate).

Compounds of this invention and the salts thereof possess centralnervous system modifying activity, particularly as depressants and aretherefore useful as tranquilizers. They may be administered orally orparenterally in the form of tablets, capsules, elixirs, injectables, or

the like, by incorporating the appropriate dosage of the compound ofFormula I or a physiologically acceptable salt thereof in a dosage rangesimilar to that used with chlordiazepoxide. The compounds of thisinvention also have been found to possess antibacterial activity.

The oXa compounds coming within the purview of this invention areprepared by reacting a 2-monolower alkylaminophenol having the FormulaII wherein R, X and p are as hereinabove defined with an acid halidehaving the Formula III wherein R, X and p are as defined above to yieldan intermediate of Formula IV This intermediate is then cyclized as bytreatment with an alkali metal hydroxide such as sodium hydroxide toform compound of Formula V The compound of Formula V is then reacted inan inert solvent, such as toluene, in the presence of a base such assodamide, potassium butoxide, powdered sodium hydroxide, and the like,with a basic halide of the formula Hal--AB wherein Hal is halogen, e.g.,chloro or bromo and A and B are as defined above, to yield the newintermediates of this invention having the Formula VI wherein R, R, A,B, X, X, p and n are as defined above.

The final products of this invention (compounds of Formula I) are thenprepared by reducing the new intermediates of this invention with areducing agent such as lithium aluminum hydride.

The compounds of this invention (compounds of Formula I) wherein Y is Smay be prepared by reducing compounds having the Formula VII wherein thesymbols are as herein described with a reducing agent such as lithiumaluminum hydride.

The corresponding sulfones and sulfoxide derivatives of Formula I maythen be prepared by oxidizing compounds of Formula I vvherein Y is Swith potassium permanganate and hydrogen peroxide, respectively.

Examples of 2-monoloweralkylphenol starting materials are:

o-methylaminophenol; o-t-butylaminophenol; o-heptylaminophenol;2-ethylamino-4-ethoxyphenol; 3,4-dichloro-2-ethylaminophenol;4-methylthio-2-propylaminophenol; 6-trifiuoromethyl-2-propylaminophenol;6-trifluoromethyl-2-rnethylaminophenol; 5-hydroxy-2-methylaminophenol;4-dimethylamino-2-methylaminophenol; 3 ,4-dimethoxy-Z-methylaminophenol;4-cyano-2-methylaminophenol; 6-nitro-2-methylaminophenol.

Examples of compounds which may be utilized as starting materialsaccording to Formula 111 are:

a-bromo-a-phenyl-acetylchloride; a-bromo-a-(Z-methylphenyl)-proponoylchloride; -bromo-p-phenyl butanoyl chloride; fl-bromo-B-phenylpropionylchloride; [3 bromo-a-heptyl-p-phenylpropionyl chloride;,G-bromo-u-phenylpropionyl chloride; 'y-bromo-B-phenylbutyloyl chloride;'y-bromo-fl-phenylvaleroyl chloride; fl-bromo-a-methyl-B-(4-methoxyphenyl) pro pionyl chloride;Ot-bI'O'Il'lO-Dt-(3-aI1'1lIlOph6I1yl.) acetyl chloride; a-bIOn'lO-u-3-chlorophenyl) acetyl chloride; a-bromo-a-(3-ethylthiophenyl)acetylchloride; oc-bIOIIlO-oc- Z-hydroxyphenyl -acetyl chloride;a-bromo-a-(6-trifluoromethyl)acetyl chloride; m-bromo-a- (4-nitrophenyl)acetyl chloride; and tx-bromo-a-(2,4,6-trichlorophenyl)acetyl chloride.

Examples of starting materials which may be utilized wherein Y is S are:

The following examples are illustrative of the invention. Alltemperatures are stated in degrees centigrade unless otherwise stated:

EXAMPLE 1 2- (Z-diethylaminoethyl) -3,4-dihydro-4-methyl-2-phenyl- 2H-l,4-benzothiazine, hydrochloride A solution of 11.0 g.2-(2-diethylaminoethyl)-4methyl- 2-phenyl-2H-1,4-benzothiazin-3 (4H)-one(B.P. ZOO-205 at 0.4 mm.) in 60 ml. of ether is added dropwise to asuspension of 1.8 g. of lithium aluminum hydride in 100 ml. of ether.This mixture is refluxed for three hours, cooled and treated with ml. ofethyl acetate, 5 ml. of

water and then with a solution of 2 g. of sodium hydroxide in ml. ofwater. This mixture is stirred for one hour, filtered and the filtratedried over magnesium sulfate. Evaporation of the dried solvent yields 10g. of the base. The latter is dissolved in ml. of ethanol, treated with3.5 ml. of 7.9 N alcoholic hydrogen chloride and diluted with ether toyield a gummy hydrochloride. The latter is triturated with fresh etherseveral times to give 10 g. of granular material. The latter isdissolved in ml. of chloroform, treated with Darco, filtered and thefiltrate poured ,onto 800 ml. of ether to give 6.8 g. of pale yellowsolid.

EXAMPLE 2 2-(2-diethylaminoethyl) -3,4-dihydro-4-methyl-2-phenyl-2H-1,4-benzoxazine, hydrochloride (A) Preparation of4-methyl-2-phenyl-2H-1,4-benzoxazine-3-(4H)-one. A stirred solution of51.0 g. of a-bromoa-phenyl-acetyl chloride in 250ml. of chloroform iscooled to 10 and treated dropwise with a solution of 27.0 g. ofo-methylaminophenol and 22 g. of triethylamine in 100 ml. of chloroformwhile maintaining the temperature at 10-20". This mixture is allowed tostand at room temperature overnight and then washed with 100 ml. ofwater (six times). The organic phase is dried over magnesium sulfate,filtered and the solvent evaporated to give 64 g. of residue. The latteris dissolved in 80 ml. of ethanol and added to a solution of 16 g. ofsodium hydroxide in 400 ml. of water at 40. The mixture is then heatedat 80-83 for twenty minutes. A heavy oil separates from the mixture. Thelatter is cooled and the oily phase solidifies. This solid is dissolvedin 500 ml. of ether, washed with 50 ml. of water several times and thendried over magnesium sulfate. After evaporation of the solvent, theresidual material weighs 31.5 g., M.P. 77. Crystallization from 100 ml.of isopropyl alcohol yields 26 g. of material, M.P. 76-78.

(B) Preparation of 2-(Z-diethylaminoethyl)-4-methyl-2-phenyl-2H-1,4-benzoxazine-3 (4H)-one. To a suspension of 2.7 g. of 50%sodium hydride in 130 ml. of dimethylformamide is added 13.0 g. ofmaterial from part A. This mixture is heated to 80, maintained at 80-85for thirty minutes, cooled and treated with a solution of 11.0 g. of2-diethylaminoethyl chloride in 40 ml. of toluene. The mixture isstirred at room temperature for one hour and then at -100 for fourhours. The solvent is removed at reduced pressure and the residue istreated with ml. of water and 100 ml. of ether. The ether phase isextracted with dilute hydrochloric acid and the latter solution thentreated with sodium hydroxide solution to liberate the base. The freebase is extracted with ether, dried over magnesium sulfate, filtered,and the filtrate evaporated. Distillate of the residue gives 60 g. ofproduct, B.P. (0.5 mm.). The citrate salt of this material melts at106-108 (from acetonitrile (C) Preparation of2-(2-diethylaminoethyl)-3,4-dihydro-4-methyl-2-phenyl-2H-1,4-benzoxazine,hydrochloride. By interaction of an ether solution of the material frompart B with a suspension of 1.0 g. of lithium aluminum hydride in etheraccording to the procedure described in Example 1, the product isobtained.

EXAMPLE 3 2-[2- (dimethylamino)ethyl] -3,4-dihydro-4-methyl-2-phenyl-2H-1,4-benzothiazine, hydrochloride Following the procedure ofExample 1 but utilizing 2- dimethylaminoethyl 4 methyl 2 phenyl 2H 1,4-

benzothiazine, 3(4H)-one in lieu of2-(2-diethylaminoethyl)-4-methyl-2-phenyl-2I-I 1,4 benzothiazin-3(4H)-one the desired product is obtained.

EXAMPLE 4 2- [3 (dimethylamino propyl -3,4-dihydro-4-methyl-2-phenyl-2H-1,4-benzothiazine, hydrochloride Following the procedure ofExample 1 but utilizing 2- 3 (3-dimethylaminopropyl)-4-methyl 2 phenyl2H 1,4- benzothiazine-3 (4H)-one in lieu of2-(2-diethylarninoethyl)-4-methyl-2-phenyl-2H 1,4 benzothiazin-3 (4H)-one the desired product is obtained.

EXAMPLE 5 2- [Z-(diethylamino) ethyl] -3 ,4-dihydro-4- 2-phenethyl)2-phenyl-2H-1,4-benzothiazine, hydrochloride Following the procedure ofExample 1 but utilizing 2-(Z-diethylaminoethyl)-4-(2-phenethyl)-2-phenyl-2H 1,4- benzothiazine-3(4H)-one in lieu of Z-(Z-diethylaminoethyl)-4-methyl-2-phenyl-2H 1,4benzothiazin 3(4H)- one the desired product is obtained.

EXAMPLE 6 2- [2-(4-morpholinyl) ethyl]-3,4-dihydro-4-methyl-2-phenyl-2H-1,4-benzothiazine, hydrochloride Following the procedure ofExample 1 but utilizing 2- [2-(4-morpholinyl)ethyl]-4-methyl 2 phenyl 2H1,4- -benzothiazine-3-(4H)-one in lieu of2-(2-diethylaminoethyl)-4-methyl-2-phenyl-2H 1,4 benzothiazin 3(4H)- onethe desired product is obtained.

EXAMPLE 7 2- (2-dimethylaminoethyl) -2,3,4,S-tetrahydro-S-methyl-2-phenyl-1,5-benzothiazepine, hydrochloride Following the procedure ofExample 1 but utilizing 2- (2dimethylaminoethyl)-2,3-dihydro-5-methyl-2-phenyll,5-benzothiazepin-4(5H)-onein lieu of 2-(2-diethylamino)-4-methyl-2-phenyl-2H-1,4-benzothiazin3(4H)- one the desired product is obtained.

EXAMPLE 8 2-[2-(4-piperidino)ethyl]-2,3,4,5 tetrahydro-5-methyl-2-phenyl-1,5-benzothiazepine, hydrochloride Following the procedures ofExample 1 but utilizing 2- [2-(4-piperidino)ethyl]-2,3-dihydro-5-methyl2 phenyl- 1,5-benzothiazepin-4(5H)-one in lieu of2-(2-diethylaminoethyl)-4-methyl-2-phenyl 2H 1,4 benzothiazin- 3(4H)-onethe desired product is obtained.

EXAMPLE 9 3- 3-dimethylaminopropyl -2,3 ,4, 5 -tetrahyd ro-2,5-dimethyl-3-phenyl-1,5-benzothiazepine, hydrochloride Following theprocedure of Example 1 but utilizing 3 (3 dimethylaminopropyl) 2,3dihydro 2,5 dimethyl 3 phenyl 1,5 benzothiazepin 4(5H) one in lieu of2-(2-diethylaminoethy1)-4-methyl-2-phenyl-2II-1,4-benzothiazin-3(4H)-one the desired product is obtained.

EXAMPLE 10 3- [2- (2-pyrrolidyl ethyl] -2, 3,4, 5 -tetrahydro-2,5-dimethyl- 3-phenyl-1,5-benzothiazepine, hydrochloride Following theprocedure of Example 1 but utilizing 3 [2 (2 pyrrolidyl)ethyl] 2,3dihydro 2,5 dimethyl 3 phenyl 1,5 benzothiazepin 4(5H) one in lieu ofZ-(Z-diethylaminoethyl)-4-methyl-2-phenyl-2H- 1,5-benzothiazin-3(4H)-onethe desired product is obtained.

7 EXAMPLE 11 2-[2-(dimethylamino)ethyl] 3,4 dihydro 2-(p-chlorophenyl) 4benzyl 6 chloro 2H-l,5-benzothiazine, hydrochloride Following theprocedure of Example 1 but utilizing 2 dimethylaminoethyl 2(p-chlorophenyl) 4-benzyl- 6 chloro 2H 1,4 benzothiazine 3(4H) one inlieu of 2-(2-diethylaminoethyl) 4 methyl 2 phenyl-2H- 1,5-benzothiazin-3(4H)-one the desired product is obtained.

EXAMPLE 12 2-[(2-diethylamino)ethyl] 3,4 dihydro 2 (p-methoxyphenyl) 4methyl 6 trifiuoromethyl-2H-1,4- benzothiazine, hydrochloride Followingthe procedure of Example 1 but utilizing 2 (2 diethylaminoethyl) 2(p-methoxyphenyl) 4- methyl 6 trifluoromethyl 2H 1,4 benzothiazine-3(4H)-one in lieu of 2-(2-diethylaminoethyl)-4-methyl- 2 phenyl 2H 1,5benzothiazin 3(4H) one the desired product is obtained.

EXAMPLE l3 2- [2 (dimethylamino) ethyl] -2, 3,4,5 -tetrahydro-S-alkyl-2- phenyl-8-bromo-1,5-benzothiazepine, hydrochloride Followingthe procedure of Example 1 but utilizing 2 (2-dimethylaminoethyl) 2,3dihydro 5 alkyl 2- phenyl-8-bromo-1,5-benzothiazepin 4(5H)-one in lieuof 2 (2-diethylaminoethyl) 4 methyl 2 phenyl 2H- 1,5-benzothiazin-3(4H)-one the desired product is obtained.

EXAMPLE 14 3 [(3-dimethylamino)propyl] 2,3,4,5 tetrahydro 5- methyl 3phenyl 7 trifiuoromethyl 1,5 benzothiazepine, hydrochloride Followingthe procedure of Example 1 but utilizing 3 (3-dimethylaminopropyl) 2,3dihydro 5 methyl- 3 phenyl 7 trifluoromethyl 1,5 benzothiazepin-4(5H)-one in lieu of 2-(2-diethylaminoethyl)-4-methyl- 2 phenyl 2H 1,5benzothiazin 3(4H) one the desired product is obtained.

EXAMPLE l5 3 [2-(pyrrolidyl)ethyl] 3,4,5,6 tetrahydro 6-methyl- 3(3-chlorophenyl) 2H 1,6 benzoxazocine, hydrochloride Following theprocedure of Example 2 but substituting 'y bromo [3(3-chlorophenyl)butyroyl chloride for 06- bromo-a-phenylacetyl chloridein part A thereof and 2- pyrrolidylethylchloride for 2-diethylaminoethylin part B thereof the desired product is obtained.

EXAMPLE 16 2- [2 morphol inyl) ethyl] -2, 3 ,4-trihydro-5-methyl-2-phenyl-1,5-benzoxazepine, hydrochloride Following the procedure ofExample 2 but substituting [3 bromo {3 phenylpropionyl chloride fora-bromo-aphenylacetyl chloride in part A thereof and2-(morpholinyl)ethyl chloride for Z-diethylarninoethyl in part B thereofthe desired product is obtained.

EXAMPLE l7 3-[2(piperidino)ethyl] -2,3,4-trihydro-5-methyl-3-phenyl-1,5-benzoxazepine, hydrochloride Following the procedure of Example 2but substituting p-bromo-a-phenylpropionyl chloride fora-bromo-a-phenylacetyl chloride in part A thereof and 2-piperidinoethyl8 for 2-diethylaminoethyl in part B thereof the desired product isobtained.

EXAMPLE l8 2- [2- (diethylamino) ethyl] -3 ,4-dihydro-4-methyl-2-phenyl-2H-1,4-benzothiazine-S-dioxide 2- [2- (diethylamino ethyl] -3,4-dihydro-4-methyl-2- phenyl-2H-1,4-benzothiazine-S-oxide Repeating theprocedure of Example 18 but utilizing hydrogen peroxide in lieu ofpermanganate, the desired product is recovered.

'EXAMPLE 20 2- [2- (diethylamino ethyl] -3 ,4-dihydro-4-methyl-2-phenyl-2H-l,4-benzothiazine, methochloride A mixture of 10 g. ofmaterial from Example 1 in 50 ml. of water is treated with 10 ml. of 10%sodium hydroxide solution and the liberated base extracted with 200 ml.of ether. The organic phase is dried over magnesium sulfate, filteredand concentrated to remove the solvent. The residue is dissolved in 50ml. of acetonitrile and treated with 20 g. of methyl chloride. Afterstanding at room temperature for a day, the mixture is refluxed for onehour and the solvent removed under reduced pressure to give the product.The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound of the formula Y(CI-[R)n A-B III-CH2(C1IR)n R wherein Y isselected from the group consisting of -S--, SO and SO-; R is selectedfrom the group consisting of lower alkyl, lower alkenyl, (X-substitutedphenyl) lower alkyl, 3,4 methylenedioxyphenyl lower alkyl, 3,4ethylenedioxyphenyl lower alkyl, furyllower alkyl, thienyl lower alkyl,naphthyl lower alkyl, pyridyl-lower alkyl, (X-substituted phenyl)-loweralkenyl, 3,4 methylenedioxyphenyl-lower alkenyl, 3,4-ethylene-dioxyphenyl-lower alkenyl, furyl-lower alkenyl, thienyl-loweralkenyl, naphthyl-lower alkenyl, and pyridyl-lower alkenyl; R isselected from the group consisting of hydrogen and lower alkyl; X and Xare the same or different and are selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy, amino, di-lower alkylamino, halo,lower alkylthio, hydroxy, cyano, nitro, trifiuoromethyl; A is loweralkylene; B is a basic nitrogen containing radical having less thantwelve carbons selected from the group consisting of amino; (loweralkyl) amino; di(lower alkyl) amino; (hydroxy lower alkyl) amino,di(hydroxy lower alkyl) amino; phenyl (lower alkyl) amino; N-(loweralkyl) phenyl (lower alkyl) amino; and saturated 5- to 7-memberedmonocyclic heterocyclic radicals of less than twelve carbon atoms selected from the group consisting of piperidino; (lower alkyl)piperidino; di(lower alkyl) piperidino; (lower alkoxy)piperidino;homopiperidino; piperidyl; (N-lower alkyl)pipe1'idyl; pyrrolidino;(lower alkyl) pyrrolidino; di(lower alkyl) pyrrolidino; (lower alkoxy)pyrrolidino;

9 10 pyrolidyl; (N-lower alkyl)-pyrrrolidyl; morpholino; (lower 3. Acompound of the formula alkyl) morpholino; di(1ower alkyl) morpholino;(lower S CH2 phenyl alkoxy) morpholino; thiarnorpholino; (lower alkyl)thiamorpholino; di(lower alkyl) thiamorpholino; (lower lower alkylalkoxy) thiamorpholino;piperazino;4-R-substituted piper- 5 lower yeazino; [hydroxyflower a1kyl)] piperazino; (lower alkyl) N CH2OH2 loweralkyl piperazino; di(lower alkyl)piperazino; (lower alkoxy)-piperazino;homopiperazino; and 4-R-substituted homopiperazino; p is an integer fromone to three, one It is one Wherem R 15 as definfid 111 clalm and theother It represents zero or one, and salts thereof. 10

References Cited 2. A compound of the formula UNITED STATES PATENTSPhenyl mwmlkyl 3,395,150 7/1968 Krapcho 260-268 S-C1owera1ky1ene-N 153,401,166 9/1968 Krapcho 260243 ower alkyl JAMES A. PATTEN, PrimaryExaminer T US. 01. X.R. R

20 wherein R is as defined in claim 1. 326-81, 999

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 3.535338Dated October 20. 1970 Inventor-(s) John Krapcho It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 2, line 3, "5- or" should read5 to-; and on line 45,

before "benzoic" insert-maleic- Column 3, first formula 1 should read(X) X P Column 3, third formula CHR should read (CHR Column 6, line 42,"2- (2-diethyl-amino" should read2- (2- diethyl-aminoethyl- SIQNED KNDSEALED m2 fiil mmaumm'm'h wmmm E. 505mm. 3

.Attesting Officer Gomissioner of Patents

